Cocaine structure

Extension of Tropine Alkaloids. Here again, medicinal chemists have gone beyond nature by molecular modification. While cocaine possesses topical anesthetic activity but no local infiltration value as an anesthetic, a number of very useful, local anesthetic agents such as procaine and lidocaine have been derived from our knowledge of the structure of cocaine. Chemists have broadened the scope of usefulness of the cocaine structure. 

The first totally synthetic substitute was eucaine. It was synthesized by Harries in 1918 and retains many of the essential skeletal features of the cocaine molecule. The development of this new anesthetic partly confirmed the portion of the cocaine structure essential for local anesthetic action. The advantage of eucaine over cocaine is that it does not produce mydriasis and is not habit forming. Unfortunately, it is highly toxic. 

Local anaesthetics following from the cocaine structure 300... 

A synthesis of ( )-cocaine proceeded through an initial cycloaddition of (526) to (527) to produce the bicyclic structure (528) (78JA3638). 

Illustrations of the variation in structure associated -ivith capacity to produce local anresthesia may be found among the numerous synthetic alkaline esters that have been introduced and used as cocaine substitutes, e.g., amylocaine (I), amydricaine (II) and benzamine (III). 

Trachelantamine, according to Syrneva, has a weak atropine-like action and also produces local anaesthesia. Its hydrolytic product, trache-lantamidine, which is structurally identical with tsoretronecanol, yields a p-aminobenzoyl derivative of -which the crystalline hydrochloride, m.p. 230-2°, is said to be as potent a local anaesthetic as cocaine hydrochloride. The chloro- -heliotridane (p. 606) formed by the aetion of thionyl ehloride on trachelantamidine reacts with 6-methoxy-8-aminoquinoline to form 6-methoxy-8-(pseMdoheliotridylamino)-quinoline,... 

Oxidation of ecgonine (2) by means of chromium trioxide was found to afford a keto acid (3). This was formulated as shown based on the fact that the compound undergoes ready themnal decarboxylation to tropinone (4)The latter had been obtained earlier from degradative studies in connection with the structural determination of atropine (5) and its structure established independently. Confirmation for the structure came from the finding that carbonation of the enolate of tropinone does in fact lead back to ecgonine. Reduction, esterification with methanol followed by benzoylation then affords cocaine. 

The observation that very significant parts of the cocaine molecule could be deleted from synthetic analogs without loss of biologic activity led to the search for the minimal structural feature consistent with activity. This exercise, sometimes referred to as molecular dissection, not only led to great simpli-fi cation of the structure of local anesthetics but resulted fi-tially in the preparation of active molecules that bear only the remotest structural relation to the prototype, cocaine. 

A chance observation made some time prior to the full structural elucidation of cocaine in fact led to one of the more important lasses of local anesthetics. It was found that the simple ethyl e. ter of p-aminobenzoic acid, benzocaine (25), showed activity. 1-. a local anesthetic. It is of interest to note that this drug, I 1rst introduced in 1903, is still in use today. Once the struc-iiire of cocaine was established, the presence of an alkanolamine iiiniety in cocaine prompted medicinal chemists to prepare esters "I aminobenzoic acids with acyclic alkanolamines. Formula 26 11 presents the putative relationship of the target substances with cocaine. 

The simplification of the local anesthetic phaimacophore of cocaine to an aryl substituted ester of ethanolamine has been described previously. Atropine (S2) is a structurally closely related natural product whose main biologic action depends on inhibition of the parasympathetic nervous system. Among its many other actions, the compound exerts useful spasmolytic effects. 

It was therefore of some interest to so modify the molecule as to maximize this particular activity at the expense of the side effects. In much the same vein as the work on cocaine, the structural requirements for the desired activity had at one time been whittled down to embrace in essence an a-substituted phenylacetic acid ester of ethanolamine (S3). 

Esters of tropine have a venerable place in medicinal chemistry. One such compound, cocaine, the object of some current interest, was the natural product lead which led eventually to most of today s local anesthetics. A distantly related analogue is prepared by reaction of tropine (132) with 3,5-dimethylbenzoyl chloride. This leads to an ester structurally related to another ]ii ominent natural product, atropine (133). The product, tropanaerin (134), is described as an iinti.serotonergic agent intended for antimigraine use [34]. 

Cocaine has been prepared by a sequence beginning w ith a Mannich reaclion (Problem 23.63) between dimethyl acetonedicarboxylate, an amine, and a dialdehyde. Show the structures of the amine and dialdehyde. 

Coal, structure of, 517 Coal tar, compounds from, 517 Cocaine, specific rotation of, 296 structure of. 64, 916 structure proof of. 875 synthesis of, 915... 

The ending caine stems from cocaine, the first clinically employed local anaesthetic. Procaine and tetracaine are ester-linked substances, the others are amides. Amide bonded local anaesthetics usually contain two i s in their name, ester-bonded only one. In the structure drawings, the lipophilic portion of the molecule is depicted at the left, the amine at the right. The asterisk marks the chiral centre of the stereoisomeric drugs. Lipid solubility is given as the logarithm of the water octanol partition coefficient, log(P). 

Cocaine and desipramine inhibit the reuptake of monoamine neurotransmitters whereas amphetamine, which is a phenylalkylamine - similar in structure to the catecholamines, see Fig. 4 - competes for uptake and more importantly, evokes efflux of the monoamine neurotransmitters. All of them exert antidepressant effects. Cocaine and amphetamine are addictive whereas tricyclic antidepressants and their modern successors are not. The corollaty of the addictive properties is interference with DAT activity. Blockade of DAT by cocaine or efflux elicited by amphetamine produces a psychostimulant effect despite the different mechanisms even the experienced individual can hardly discern their actions. Because of the risk associated with inhibiting DAT mediated dopamine clearance the antidepressant effects of psychostimulants has not been exploited. 

Chemical Structures. Figure 1 shows the chemical structures for 14 phenylethylamine compounds. Nine of these compounds are used clinically as anorectics (ii-amphetamine, phentermine, diethylpropion, phenmetrazine, phendimetrazine, clotermine, chlorphentermine, benzphetamine, and fenfluramine). Four of these compounds are not approved for clinical use and are reported to have hallucinogenic properties (MDA, PMA, DOM, and DOET). The final compound ( /-ephedrine) is used clinically for bronchial muscle relaxation, cardiovascular, and mydriatic effects. Figure 2 shows the chemical structure for MDMA, the methyl analog of MDA. MDMA is not approved for clinical use and has been reported to produce both LSD-like and cocaine-like effects. 

The neuroehemical sites for psyehomotor stimulant reward are likely to be the presynaptic dopamine terminals located in the region of the nucleus aeeumbens, frontal cortex, and other forebrain structures that originate in the ventral tegmental area. Note, however, that intraeranial self-administration of eoeaine is elicited from the frontal cortex, but not from the nucleus aeeumbens (Goeders and Smith 1983). Thus, eoneomitant activation of structures other than the nucleus accumbens may be an important part of the circuitry involved in initiation of cocaine intravenous self-administration, as has been hypothesized for the opiates (Smith and Lane 1983 Smith et al. 1982). 

Reith, M.E.A., Meisler, B.E., Sershen, H., and Lajtha, A., Structural requirements for cocaine congeners to interact with dopamine and serotonin uptake sites in mouse brain and to induce stereotyped behavior, Biochem. Pharmacol., 35, 1123, 1986. 

Mash, D.C. and Staley, J.K. Cocaine recognition sites on the human dopamine transporter in drug overdose victims. In Neurotransmitter Transporter Structure and Function, Reith, M.E.A., Ed. Humana, New York, 1996, 56. 

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

The answer is local anesthetic properties it can block the initiation or conduction of a nerve impulse. It is biotransformed by plasma esterases to inactive products. In addition, cocaine blocks the reuptake of norepinephrine. This action produces CNS stimulant effects including euphoria, excitement, and restlessness Peripherally, cocaine produces sympathomimetic effects including tachycardia and vasoconstriction. Death from acute overdose can be from respiratory depression or cardiac failure Cocaine is an ester of benzoic acid and is closely related to the structure of atropine. 

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